Uterine leukemia inhibitory factor (LIF), heparin-binding epidermal growth factor-like growth factor (HB-EGF), Hoxa-10 and cyclooxygenase-2 (COX-2) are essential to implantation success. The proposed hypothesis is that these genes participate in embryo-uterine interactions during implantation in a concerted manner via novel signaling pathways. Specific aims are to determine in the mouse that: (1) an interaction of uterine EGF-like growth factors with the blastocyst EGF family of receptors is a prerequisite for the initiation of implantation; (2) prostaglandins (PGs) generated by the COX-2 pathway are involved in initiating implantation and subsequent decidualization; (3) PG synthesis is regulated in a spatiotemporal manner in the uterus; (4) PG effects on implantation and decidualization are mediated by nuclear receptors in the uterus; (5) further validation of the importance of the PG signaling pathway in these processes can be achieved using LIF and Hoxa-10 mutant mice. Several knockout mouse models with known defective implantation processes will be manipulated experimentally by molecular, cellular, biochemical and physiological techniques. The proposed research addresses two important global concerns on women's health issues: infertility and rapid population growth. Events of preimplantation embryo development and preparation for implantation are two of the major determinants of these concerns. Basic research to better understand these events will help alleviate problems of infertility, and aid in the development of new and improved contraceptive methods.